Neurology

Neurosurgery is now an effective treatment option for some patients with epilepsy When a seizure disorder persists despite optimum drug therapy and significantly affects quality of life, surgical treatment should be considered. Many patients with severe refractory epilepsy can benefit from appropriate surgery and should be given this option by timely referral and investigation. Extrapolating US studies,1 there are probably several thousand eligible people in Australia. In the past, operations were confined to removal of obvious structural causes of seizure, such as tumours or post-traumatic scars. Over the past 50 years, it has become increasingly apparent that there are many patients with persisting epilepsy who could benefit from surgical resection of foci previously difficult to define. The development of increasingly precise methods of anatomical and functional seizure localisation has expanded this group. The evidence for effectiveness of surgery for epilepsy can be seen by outcome studies comparing patients who have had surgery with patients who have had long-term medical therapy. An important recent Canadian study2 of 80 patients refractory to at least two anticonvulsants who were randomly assigned to either undergo temporal lobe surgery or receive further drug treatment showed clear statistical evidence of the success of surgery. At one year, 58% of patients in the surgical group and 8% in the medical group were free of seizures. It should be noted that four patients had adverse effects of surgery, including one small thalamic infarct, one wound infection, and reduced verbal memory in two cases. One patient in the medical group died. Not all patients with refractory epilepsy can be treated surgically. A prerequisite for successful surgery for epilepsy is the precise definition of a discrete seizure focus involving an area of cortex amenable to safe excision. Psychiatric and social factors must also be taken into account. The sequence of events leading to surgery will usually include a period of video electroencephalography (EEG) to define and localise the seizure syndrome, magnetic resonance imaging (MRI), and localisation of eloquent cortex (ie, functional [speech or motor] cortex) by neuropsychological or functional testing. Intraictal single-photon emission computed tomography (SPECT) scanning of regional blood-flow changes is an extremely useful tool for confirmation of a seizure focus. Where available, positron emission tomography is helpful to correlate abnormal glucose metabolism with areas of anatomical abnormality. Anterior temporal lobectomy with hippocampectomy is the most commonly performed surgical procedure for treating epilepsy (see Box). This is because the procedure has a high rate of cure or significant reduction of seizures in patients with complex partial seizures due to hippocampal sclerosis, the largest group of suitable patients. The long-term result of this operation, performed on appropriately selected patients, is that about 70% of patients will become seizure-free.3 Resection of areas of cortical dysplasia has been performed more frequently in recent years, as this condition can now usually be defined with MRI. Where cortical dysplasia occurs close to motor or language areas of the cortex, surgery is often performed under local anaesthesia so that motor function or speech can be monitored by cortical stimulation, reducing the risks of postoperative paresis or dysphasia. In addition, electrocorticography (EEG recorded directly from the cortex), performed either acutely, during surgery, or electively, after placement of subdural electrodes, can further define the boundary between functional and non-functional cortex. Image-guided surgery linked to MRI has enhanced the accuracy and safety of cortical excision. Hemispherectomy is the most successful form of excisional surgery. This major procedure is occasionally indicated for young patients with developmental or acquired affections of one hemisphere leading to catastrophic and continued seizure patterns, although it constitutes a high-risk procedure. Many of these patients make a good recovery once their seizures are eliminated. Corpus callostomy or vagotomy are palliative procedures that may benefit some patients with severe generalised seizure patterns. The former may also be helpful (although rarely curative) in some patients with atonic seizures or drop attacks. Chronic stimulation of the left vagal nerve via a subcutaneous stimulator linked to electrodes placed in the cervical region is a low-risk, albeit expensive, procedure that reduces seizure frequency in about 50% of patients with otherwise untreatable severe epilepsy. A small group of patients with hypothalamic hamartomas leading to the syndrome of gelastic ("laughing") epilepsy may now be treated successfully surgically using an image-guided technique via the third ventricle.4 Postoperatively, adequate support systems are extremely important. Most patients will require ongoing anticonvulsant treatment for two or more years. Mortality and major morbidity after surgery for epilepsy are nowadays low: mortality is less than 0.5% and hemiparesis and hemianopia occur in less than 2% of cases.5 Devastating memory disorders following temporal lobectomy can be avoided by appropriate patient selection and preoperative neuropsychological testing. For example, verbal memory deficits suggesting a left or dominant hippocampal lesion would contraindicate a right hippocampal resection. Considering the poor long-term prognosis for patients with refractory seizures, appropriate surgery has unequivocal advantages. In addition to the social and psychological benefits to the individual, cost–benefit analysis has demonstrated the advantages of surgical treatment compared with life-long medical management.6 The requirements for input from various specialists and the need for particular investigative techniques means that such patients should be assessed in Comprehensive Epilepsy Centres. Some notable contributions to the development of surgery for epilepsy have come from Australia and New Zealand.7-9 There are many more Australians who could benefit from surgical treatment, and this option should be considered by those caring for patients whose seizures continue to be disabling despite best medical treatment.

Gavin C A Fabinyi FRACS

Objective: To summarise recent evidence from case reports (published January 1995 – September 2001) of adverse events after cervical spine manipulation.Data sources: Five computerised literature searches (MEDLINE – Pubmed; EMBASE, the Cochrane Library, AMED [Allied and Complementary Medicine Database], and CISCOM [Centralised Information Service for Complementary Medicine]) were performed. No language restrictions were applied.Study selection: All case reports containing original data of adverse events after cervical spine manipulation were included.Data extraction: All articles were evaluated and key data extracted according to pre-defined criteria: patient's age, sex and diagnosis; type of therapist; type of treatment; nature of adverse event; method of diagnosis; and clinical outcome.Data synthesis: Thirty-one case reports (42 individual cases) were found. The patients were equally distributed between the sexes (21 male, 20 female, one unknown) and mostly middle-aged (range, 3 months to 87 years). Most were treated by chiropractors. Arterial dissection causing stroke was reported in at least 18 cases.Conclusions: Serious adverse events after cervical spine manipulation continue to be reported. As the incidence of these events is unknown, large and rigorous prospective studies of cervical spine manipulation are needed to accurately define the risks.

Edzard Ernst MD, PhD, FRCP(Edin)

The impact of stroke remains considerable, despite a modest decline in case fatality1 and an encouraging reduction in incidence on the west coast of Australia during the past decade.2 To the optimists among us, it appears that some efforts, particularly in public health and primary care, are paying off. However, population risk-factor surveys indicate that, although the prevalence of smoking has declined, the prevalences of hypertension and hypercholesterolaemia have changed minimally and the prevalences of obesity and diabetes have increased dramatically over the past decade.1,3 The role of the general practitioner is pivotal in identifying and managing these risk factors. The Avoid Stroke as Soon as Possible (ASAP) general practice stroke audit, published in this issue of the Journal (page 312),4 provides further evidence that modifiable risk factors for stroke and vascular disease are highly prevalent in the Australian community. Importantly, the ASAP audit has measured the prevalence of atrial fibrillation and transient ischaemic attack (TIA). These factors are unique to stroke pathophysiology and are associated with high absolute risk, but have received limited attention in previous risk-factor surveys. Sturm et al reviewed 16 148 general practice consultations surveyed from a random sample of 321 GPs across five States. Seventy per cent of patients aged 30 years or more had at least one major risk factor; 34% had two or more. Not surprisingly, hypertension (44%) and hypercholesterolaemia (43%) were the most prevalent modifiable factors. Importantly, the proportion of older patients at high absolute risk was considerable. For example, among the men, 14% aged 70–79 years and 16% aged over 80 years had atrial fibrillation. Reliable measurement of the occurrence of TIA is more difficult given the variability in presentation and clinical assessments. However, the figure of 4% for any history of TIA is valuable information and provides a baseline for further assessments. The high prevalence of vascular risk factors identified in the ASAP survey highlights the potential value of screening during all routine general practice consultations to identify individuals with high absolute risk of stroke. The use of absolute-risk estimates in guiding therapeutic decision making is a well-established paradigm and is being adopted increasingly often in national and international vascular disease management guidelines.5 The value of risk stratification is highlighted by the exercise of choosing the most appropriate antithrombotic agent for primary stroke prevention in atrial fibrillation. Although the risk of first stroke in atrial fibrillation averages 5% per year, risk varies from 1% or less per year up to 12%, depending on additional clinical characteristics.6 At 1% risk, any benefit from anticoagulation therapy would be nullified by the approximately 1% risk of major bleeding events. Antiplatelet therapy would be the more appropriate option in this setting. In contrast, at 12%, the reduction in risk of thromboembolic events achieved with anticoagulation far outweighs the risk of adverse bleeding events. In this setting, warfarin shows a clear net benefit and would be more appropriate. Absolute risk translates readily into clinically useful statistics, such as "number needed to treat" at the bedside, and, at the population level, the recently proposed "population impact number".7 At a practical level, however, owing to the complexity of interacting risk factors, risk stratification typically requires decision-assistance charts or computer programs (generally based on Framingham risk estimates).8,9 At present, such systems are still under evaluation or just beginning to be adopted in general practice. From the cost–benefit perspective, in the absence of a framework for risk stratification, identifying relatively low-risk populations with isolated risk factors increases the possibility that expensive drug therapies will be used as first-line options when low-cost, non-pharmacological interventions would be more appropriate. An example is a 58-year-old woman with moderate hypertension (repeated blood pressure readings 160/95 mmHg) and no other risk factors. Her absolute risk of stroke is 1.5% over five years.10 Although she is a potential candidate for antihypertensive drug therapy, the low absolute risk may suggest to the patient there is questionable value in complying with prolonged drug therapy with its attendant side-effects. It indicates to the clinician that the number needed to treat over five years in this type of patient exceeds 120 to prevent one stroke.11 Accepting the various difficulties and risks associated with screening in general practice, combining a "high risk" approach and an appropriately organised "mass" approach is likely to have a much greater impact on the overall burden of vascular disease. This combination helps minimise the problem of focusing efforts on very cost-effective treatment of small populations at high risk while ignoring the larger subgroup of the population at moderate risk, from where most vascular events emerge. Low-risk groups would also benefit from further surveillance for progression into higher-risk categories. The ASAP stroke audit provides further evidence that considerable opportunity exists to reduce the burden of stroke and other vascular diseases. Quite rightly, the authors emphasise the importance of making the most of this opportunity. However, a prerequisite for success is a framework to facilitate rational use of interventions, balancing absolute risk and potential benefit at both the individual and population levels. Although debate continues about the best decision-assistance tool to be used, any system will need to be simple and practical to use within the time and resource constraints of an already overburdened primary healthcare sector.

Christopher R Levi FRACP · Parker J Magin FRACGP · Balakrishnan R Nair FRCP, FRACP

Objectives: To determine the prevalence of stroke risk factors in a general practice population and to identify pharmacotherapies currently used in management of stroke risk factors.Design: Multicentre, observational study by 321 randomly selected general practitioners who each collected data on 50 consecutive patients attending their surgery.Patients and setting: 16 148 patients aged 30 years or older attending general practices across Australia during 2000.Outcome measures: Prevalence of hypertension, current smoking, diabetes, hypercholesterolaemia, atrial fibrillation, recent history of stroke or TIA; extent of pharmacotherapy use in risk-factor management.Results: 70% of patients had one or more risk factors and 34% had two or more. Hypertension was the risk factor with greatest prevalence (44%), followed by hypercholesterolaemia (43%) and current smoking (17%). The prevalence of risk factors generally increased with age, except for current smoking, where a decrease with age was seen. The most common pharmacotherapies were cardiovascular agents, followed by antiplatelet agents. Two-thirds of patients with hypertension were taking cardiovascular drugs, most commonly angiotensin-converting enzyme inhibitors.Conclusions: Stroke risk factors are highly prevalent in general practice patients and GPs are ideally placed for opportunistic case-finding. There is considerable scope for improving management of stroke risk factors. The Avoid Stroke as Soon as Possible (ASAP) general practice stroke audit provides a baseline against which progress in risk-factor management can be measured.

Jonathan W Sturm MB ChB, FRACP · Geoffrey A Donnan MD, FRACP · Stephen M Davis MD, FRACP · John G O'Sullivan MB BS, FRACGP · Miriam E Vedadhaghi BSc, PostGradDipNutr

Trial: PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033-1041. QuestionIn patients with a history of stroke or transient ischaemic attack, can further stroke be prevented by lowering blood pressure, even when it is not elevated? Trial details Design: Multicentre, randomised, double-blind, placebo-controlled trial with a mean 3.9-year follow-up. Setting: 172 centres in 10 countries including Asia, Australasia and Europe. Patients: 6105 patients, mean age 64 years, in stable condition after a stroke or transient ischaemic attack within the previous five years and with no definite indication or contraindication to an angiotensin-converting-enzyme (ACE) inhibitor. Intervention: In 3051 patients, a flexible blood-pressure-lowering regimen based on the ACE inhibitor perindopril (4 mg daily), with the addition (in 58% of actively treated patients) of the diuretic indapamide (2.5 mg daily, or 2 mg daily in Japan), at the discretion of the treating physicians. Matching placebo in 3054 patients. Main outcome measures: All strokes (fatal or non-fatal); secondary measures included fatal or disabling stroke, total major vascular events (non-fatal stroke, non-fatal myocardial infarction, vascular death), total and cause-specific deaths, hospital admissions, and (not reported yet) dementia and cognitive function. Main results: Active treatment reduced blood pressure by a mean of 9/4 mmHg. Against a background of standard treatment, over four years active therapy reduced strokes from 14% in those assigned placebo to 10% (relative risk reduction, 28%; 95% CI, 17%–38%, P < 0.0001). Risk reduction was similar in those who were normotensive or with baseline systolic and diastolic blood pressures ≥ 160 or ≥ 90 mmHg, respectively, irrespective of any treatment. Active therapy also reduced the risk of total major vascular events by 26% (95% CI, 16%–34%; P <0.0001) and major coronary events by 26% (95% CI, 6%–42%). After initial screening for tolerance during a four-week run-in, only 1% more patients stopped active therapy than those stopping placebo because of hypotension. In a subgroup analysis, combination therapy, but not monotherapy, had a significant benefit. In absolute terms, one in every 11 patients given combination therapy avoided death, myocardial infarction or stroke over five years of treatment. Conclusion: Blood pressure lowering was beneficial; in the trial context, perindopril plus indapamide (but not perindopril alone) prevented stroke and major vascular events in patients whose condition was stable after a previous stroke or transient ischaemic attack. CommentaryRationale for the trialAbout one in five stroke survivors suffer another stroke in the five years after the initial incident.1 Blood pressure is related in a continuous manner to the risk of an initial stroke, but many strokes occur in individuals with normal blood pressure. However, there are fewer data on the relationship between blood pressure and recurrent stroke. Systematic reviews of randomised trials of blood-pressure-lowering drugs in patients with hypertension who do not have clinical evidence of cerebrovascular disease show that sustained lowering of blood pressure reduces risk for stroke by about a third.2 Fewer data are available on the effect of lowering blood pressure in individuals with a history of cerebrovascular disease. Trial methodsImportantly, the trial tested the effect of treatment in patients with a wide range of entry blood pressures, including those who were normotensive, defined as systolic blood pressure less than 160 mmHg and diastolic blood pressure less than 90 mmHg. Because of this, the results of the trial are more generalisable than if it only included patients with hypertension. The design also allowed for clinician choice for single or combination therapy. The predefined outcomes were adjudicated by an expert committee and were deemed to be clinically relevant. Randomisation was appropriate with stratification for known prognostic factors. The sample-size estimates were robust and based on worthwhile and plausible differences in stroke rates. Analysis was on an intention-to-treat basis and subgroup analyses were prespecified. Both absolute benefits as well as relative-risk reductions were reported. New informationThe study establishes the value of blood pressure lowering to prevent recurrent stroke (both ischaemic and haemorrhagic). In particular, it demonstrates the role of blood pressure lowering for secondary prevention of stroke in normotensive patients. PROGRESS is the first study to show benefit for Asian as well as white populations. The trial also showed that blood pressure lowering can prevent coronary events in patients with previous stroke, and that blood pressure lowering was safe at least two weeks after a stroke or transient ischaemic attack. Implications for clinical practiceIn patients who have just had a stroke (irrespective of their age, whether they are hypertensive or normotensive and whether they have sustained ischaemic or haemorrhagic stroke), after two weeks, or when their condition is judged to be clinically stable, blood-pressure-lowering intervention should be considered. In those who have had a stroke at some time in the past, treatment should similarly be considered. In some patients, such as those with bilateral carotid occlusive disease, there may be some risks, and the trial does not provide information relating to these. However, in most patients, ACE inhibitor therapy could be started initially at the time of discharge or at postdischarge follow-up. However, to maximise the blood-pressure-lowering effect, most patients should receive combination therapy. The trial provides data to support use of a combination of perindopril and indapamide. PROGRESS does not provide data to show that other ACE inhibitors, other diuretics or other classes of antihypertensives would have the same demonstrable quantitative effects, nor was it designed to provide information on specific target blood pressure levels.

Andrew M Tonkin MB BS, MD, FRACP

Several recent developments in the basic and applied sciences have been incorporated into neurological and neurosurgical practice. Diagnosis. New magnetic resonance imaging (MRI) and molecular technologies have facilitated neurological diagnoses. Diffusion-weighted MRI (DWI) is the most sensitive imaging technique for acute brain lesions (eg, infarction), and distinguishes acute from chronic lesions. Coupling DWI with perfusion-weighted MRI (PWI) promises to identify which ischaemic stroke patients benefit from thrombolysis. Magnetic resonance spectroscopy, which detects metabolites (eg, lactate, choline) and N-acetyl-aspartate (NAA), can distinguish tumours (high in choline) from infarcts (low NAA and normal or low choline levels). Functional MRI (fMRI), which combines anatomical with physiological imaging, allows preoperative planning for resecting lesions in functionally important brain regions. Anatomical imaging by MRI, combined with functional imaging by ictal single- photon-emission computed tomography (SPECT) and interictal positron-emission tomography (PET), aids video-electroencephalogram monitoring and clinical assessment in localising seizure foci. The chromosomal position of many genes which, when mutated, cause neurological disorders is now known. In some (eg, Huntington's disease, muscular dystrophy, childhood-onset generalised primary dystonia), the genes, their disease-causing mutations, and gene products have been characterised. This has facilitated the development of new diagnostic techniques, implementation of predictive testing and genetic counselling services, and promise of novel approaches to treatment and prevention.1 Treatment. For patients with chronic tension-type headaches, the combination of antidepressant medication and stress management therapy is more effective than monotherapy.2 Among the newer specific acute migraine therapies, the triptans are of comparable efficacy, but differ in their onset and duration of action and adverse effect profile. Sodium valproate is an effective prophylactic for migraine. Ischaemic stroke patients benefit from 300 mg aspirin immediately or intravenous thrombolysis within three hours of onset. Anticoagulation with heparins causes 20 more deaths per 1000 patients treated (mainly intracranial haemorrhage) than aspirin, despite preventing 10 more symptomatic deep venous thromboses per 1000 patients treated. Stroke care by a multidisciplinary team in a stroke unit maximises survival free of handicap. The treatment of focal spasticity and dystonias has been revolutionised by botulinum toxin injections into affected muscle groups. The benefit lasts about 3–5 months, after which the injections can be repeated. In early Parkinson's disease, dopamine agonist monotherapy controls symptoms in a third of patients for up to five years, with fewer motor complications than with levodopa therapy. For other patients, levodopa remains the most effective symptomatic treatment. In patients with motor fluctuations due to "wearing off" of pharmacotherapy, "on" time may be increased by 10%–25% with slow-release levodopa, dopamine agonists, and catechol-o-methlytransferase inhibitors. Amantadine is an effective form of chemical pallidotomy for dopa-induced dyskinesia. In some patients, neurosurgical interventions may alleviate drug-resistant tremor and control parkinsonian symptoms. Frameless stereotaxy enables neurosurgeons to navigate and operate safely in high-risk areas of the brain. Neuroendoscopy is used in the ventricular system (eg, to remove dislodged shunt tubes, intraventricular blood, and colloid cysts, and to treat obstructive hydrocephalus by ventriculostomy) and assist trans-sphenoidal pituitary surgery. Prevention. For patients with a history of transient ischaemic attack or stroke of any type (and no contraindication to blood-pressure-lowering therapy), gradually introducing antihypertensive medication, to slowly lower blood pressure by at least 9/4 mmHg, reduces the risk of recurrent serious vascular events by at least a quarter.3 Interventional neuroradiology offers potential strategies for stroke prevention with techniques such as coiling of intracranial aneurysms and carotid angioplasty and stenting for patients with symptomatic severe carotid stenosis.4 Several newer anti-epileptic drugs (lamotrigine, topiramate, vigabatrin, gabapentin, tiagabine) have been approved as "add-on" agents in patients who have seizures despite conventional first-line treatment. For patients with temporal lobe epilepsy refractory to anti-epileptic medication, surgical resection of a part of the temporal lobe improves the proportion of patients seizure-free at one year from 8% to 58% (P < 0.001), and improves quality of life.5 For patients with multiple sclerosis who have at least two disabling relapses every two years, interferon betas reduce the relapse rate by a third, and may delay the progression of disability. Glatiramer acetate and mitoxantrone, a new immunomodulatory drug, also reduce relapses and possibly delay the progression of disability.

Graeme J Hankey MB BS, MD, FRCP, FRCPEdin, FRACP

Editorial Schizophrenia today Improvements in treatment need to be built upon and applied more widely and effectively MJA 2000; 172: 470-471 Schizophrenia Awareness Week (21-27 May) has been running in Australia since 1981. During the past 19 years some of the original goals of the week have been achieved largely thanks to the efforts of the State-based Schizophrenia Fellowships and the mental health advocacy and education organisation SANE Australia. These goals have included getting the word "schizophrenia" into the public domain, educating the community about the treatability of the disorder, and encouraging groups of carers to work together to provide mutual support and to lobby governments for enhanced services for people suffering from psychotic disorders. Today, treatment is much more likely to occur in the community, allowing patients to retain a much-valued independence (although loneliness and ennui often develop in the absence of appropriate social supports). Today, medication options are also wider, with clozapine having been used by nearly 10 000 Australians with treatment-resistant disorders (Clozaril Patient Monitoring System, Mental Health Research Institute, Melbourne, unpublished data), and other dopamine and serotonin antagonist drugs, such as risperidone and olanzapine, finding an important role because of their fewer extrapyramidal side effects and, probably, better neurocognitive outcomes.1,2 Our understanding of the biology of schizophrenia has progressed, despite the absence of a signature pathophysiology. This understanding has evolved in light of growing evidence that the disorder is associated with disturbances of neural connectivity and neurodevelopment, and abnormalities in dopaminergic, serotonergic, GABAergic and glutamatergic neurotransmission, involving particular brain regions, including the hippocampus, ventral striatum, and prefrontal cortex.3,4 Nonetheless, schizophrenia remains one of the most stigmatised of all disorders. That the term often conjures up sentiments of derision rather than compassion is well illustrated by a recent description of the Federal Government's actions towards certain UN committees as ". . . at times, sycophantic, abusive, schizophrenic and downright childish".5 The extensive and enduring impact of schizophrenia and related psychiatric disorders on the lives of affected Australians has been brought into sharp focus by a recent Commonwealth Government-sponsored National Survey of 980 individuals with psychotic disorders, more than 60% of whom had schizophrenia.6 It found that the average duration of symptoms was 15 years; 47% of participants were judged to be seriously impaired, 58% were socially withdrawn and 72% did not have a regular job. In addition, the prevalence of tobacco use (males 73%, females 56%), alcohol misuse or dependence (30%), and dependence on or misuse of street drugs (cannabis 25%; others, including heroin, 13%) was considerably higher than in the general population. However, a significant minority of patients -- approximately 25% -- have only one or two episodes of illness, do not continue to need mental health services, and have lower levels of symptoms, impairment and disability. Other data indicate that the rate of suicide among people with schizophrenia is approximately 10 times higher than that in the general population.7 One troubling response to data such as these has been a call -- based on a prediction that Australian mental health budgets are likely to remain relatively fixed -- for reduced emphasis on the treatment of psychotic disorders because of their chronicity and perceived intractability, and for transfer of resources to disorders such as anxiety and depression, which are associated with better responses to treatment.8 An alternative, and in our view far preferable, response is to concentrate on strategies which use what data we have to press for greater overall funding for mental health. There is a strong case for this, as mental illnesses account for 13% of Australia's health burden, third in importance after heart disease and cancer.9 Further, there are several sources of optimism that such strategies will be successful and that new funding is obtainable. For example, prior to 1993, mental health was almost exclusively the preserve of the States and Territories, with the Commonwealth contributing only to Medicare and pharmaceutical benefits. However, since the First National Mental Health Plan, in 1993, the Commonwealth Government has become a significant contributor to public sector psychiatric programs, allocating more than $595 million to them over the years 1993-2003. Also, the States and Territories increased their funding by more than 14% in real terms between the 1992/93 and 1996/97 financial years.10 Another cause for optimism is that, even with high-disability disorders like schizophrenia, there are many measures that meaningfully improve the quality of life of affected individuals, but which need to be better applied. These include early intervention,11 community-based rehabilitation programs, family psychoeducational programs, a greater but targeted use of the newer antipsychotic drugs,12 and good access to residential disability support services and public housing. General practitioners, especially those able to work in conjunction with specialist mental health teams, are in a position to play key roles in ensuring that their patients are offered such treatments and services. This is because people with psychotic disorders often attend GPs (eg, more than 80% had attended their GP in the 12 months before being interviewed in the National Survey,6 with a median of five attendances during that time). The Consultation Liaison in Primary Care Practice (CLIPP) Program13 is one of a number of successful models of collaboration between GPs and mental health services that provide substantial benefit to patients. Future improvements in the management of schizophrenia will require better communication and coordination between patients and carers, medical practitioners, mental health services, and non-government agencies. It will also require the development of new services, the refinement and strengthening of existing ones, especially in the psychosocial domain, the discovery of prognostic markers, and the introduction of novel pharmacotherapies. Fundamental and applied research will be essential to the successful achievement of many of these outcomes. David L Copolov Director, Mental Health Research Institute of Victoria, and Professor, Department of Psychiatry, University of Melbourne, and Professor, Department of Psychological Medicine, Monash University Bruce S Singh Cato Professor, and Head, Department of Psychiatry, University of Melbourne and Clinical Director, North West Mental Health Program Green MF, Marshall BD Jnr, Wirshing WC, et al. Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psych 1997; 154: 799-804. Purdon SE, Jones BD, Stip E, et al. Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia. Arch Gen Psychiatry 2000; 57: 249-258. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122: 593-624. Copolov DL, Velakoulis D, McGorry PD, et al. Neurobiological findings in early phase schizophrenia. Brain Res Brain Res Rev 2000; 31: 157-165. Lewis P. A McEnroe of a nation, but without the charm [letter]. The Melbourne Age 2000 3 April: 14. Jablensky A, McGrath J, Herrman H, et al. People living with psychotic illness: an Australian study 1997-98, an overview. Canberra: Mental Health Branch, Commonwealth Department of Health and Aged Care, October 1999. Harris EC, Barraclough B. Suicide as an outcome for mental disorders: a meta-analysis. Br J Psychiatry 1997; 170: 205-228. Andrews G. Efficacy, effectiveness and efficiency in mental health service delivery. A N Z J Psychiatry 1999; 33: 316-322. Mathers C, Vos T, Stevenson C. The burden of disease and injury in Australia. Canberra: Australian Institute of Health and Welfare, November 1999. National mental health report 1997: 5th annual report: changes in Australia's mental health services under the National Mental Health Strategy 1996/97. Canberra: Department of Health and Family Services, 1998. McGorry PD, Krstev H, Harrigan S. Early detection and treatment delay: implications for outcome in early psychosis. Curr Opin Psychiatry 2000; 13: 37-43. Lehman AF, Steinwachs DM and the Co-investigators of the PORT Project. At issue: translating research into practice: the schizophrenia patient outcomes research team (PORT) treatment recommendations. Schizophr Bull 1998; 24: 1-10. Meadows G. Establishing a collaborative service model for primary mental health care. Med J Aust 1998; 168: 162-165. Make a comment

David L Copolov · Bruce S Singh

Editorial Migraine treatment and mistreatment: primum non nocere Triptans can provide wonderful relief from migraine, but must not be overused as "pseudo-preventives" MJA 2000; 172: 412-413 If the 1990s was the decade of the brain for neuroscientists, then it was the decade of new treatments and renewed hope for sufferers of neurological diseases. Neurology, long the bastion of diagnosis, has become the specialty of the physician that we would all like to be -- one who is able to take a careful history and conduct a meticulous physical examination leading to a diagnosis and management plan. For headache patients, and perhaps neurological patients in general, it is the latter development in neurology, the move to more effective management of the conditions, that has been truly marvellous. We have started to identify the genes involved in causing the problem,1 and by so doing have begun to understand the episodic nature of the attacks in terms of ion-channel dysfunction. We have finally begun to image the primary headaches with functional/anatomical methods that have pointed to the brainstem, in migraine,2 and the posterior hypothalamus, in cluster headache,3 as likely candidates for the basic pathophysiological process. What is misuse and when is good medicine slipping into overtreatment? Best of all, from a clinical perspective, neurotherapeutics leapt ahead. The advent of the triptans (serotonin agonists) was to migraine and cluster headache almost the equivalent of penicillin to bacterial infection! It seems almost outrageous to liken the development of triptans to the discovery of penicillin, but this analogy has been used by at least three of my patients, themselves general practitioners who suffer migraines, to describe the change in their lives. Migraine never threatens life, but, as Professor Jim Lance, the Australian doyen of migraine, taught me, it simply "makes it hell". Disability is the key word to understanding the impact of migraine: inability to work effectively, care for dependants, enjoy recreation or participate in the myriad responsibilities that the non-migraineur takes for granted. What have we learnt from the developments of the past decade and what should we expect for the next decade in terms of therapeutics? The first triptan to be released was sumatriptan, developed in considerable part through the pioneering work of Lance and Anthony at Prince Henry Hospital in Sydney.4 This compound burst on to the clinical scene in the late 1980s,5 proving to be highly efficacious in clinical studies.6 Its development was marked by careful clinical trials methodology and spurred the widespread adoption of the International Headache Society Diagnostic Criteria7 for use in clinical studies. These criteria have been a boon for the clinical scientist and, if more widely used and adapted for primary care, could be useful for both doctors and patients more generally. As it became obvious that sumatriptan heralded a major advance in therapy, other researchers became interested in the field and triptan sons and cousins were soon in gestation. Naratriptan and zolmitriptan are now available in Australia and in Europe we also have rizatriptan; in late development or close to registration are almotriptan, eletriptan and frovatriptan. Do we have enough? For patients who respond to the triptans already available, obviously yes; for those who still suffer, confined like children to a room without a view for no sin other than their parents' genetic gifts, obviously not.8 Triptans are not perfect: a third of patients taking them have recurrence of headache within 24 hours; for some they do not work at all; and for those with significant risk factors for cardiovascular disease they are inappropriate. It has been at once heartening to find patients who show no improvement with one triptan yet respond to another, and disheartening that we have not been able to dissect what it is about the compounds9 that makes such profound differences in their clinical performance in individuals. In medicine almost every sunny day has a cloud on the horizon, and headache therapeutics is no exception. Ten years after the release of sumatriptan for clinical use, we have begun to appreciate the problems of mistreatment with triptans, reinforcing previous observations on mistreatment with other acute attack medications such as ergotamine or compound analgesics. In this context, "mistreatment" implies the inappropriate use of acute attack therapies by patients, either acting independently or under their doctors' instructions. This is referred to in the literature variously as "abuse", "overuse" or "misuse". Patients seldom misuse medications for any gain other than to attempt to function normally, to get to work or to look after their families. Given that acute medicines were designed for relatively infrequent use, and indeed that the triptans were studied explicitly in people having migraine frequencies of six or less per month, I believe that frequent use is a misuse of the medicine and a mistreatment of migraine. Reports of triptan misuse10,11 come as no surprise given the problems with ergotamine over the years,12 and this has sparked renewed interest in the subject of analgesic misuse.13 While the extent to which analgesics, particularly compound analgesics such as those containing codeine, can induce headache is not yet established, it seems clinically plausible that they block the frequency-reducing benefits of headache preventive therapy. What is misuse and when is good medicine slipping into overtreatment? With regard to ergotamine, a recent European consensus statement recommends, with some clearly stated exceptions, that the maximum usage should be 4-6 times a month.14 The tool with which to define this problem is the diary: a simple record of the number of days on which headache is experienced, and which prescription or over-the-counter medications are taken, will soon reveal whether excess medication is being consumed and whether management, including neurological referral, is appropriate. What are the prospects for the future? An understanding of migraine neurobiology will build on what has been done; more genes will be identified; functional imaging will better define and elaborate on the brain areas responsible for the disorder; and experimental laboratory work will put these observations under the modern anatomical and physiological microscope, returning more questions to the clinical scientists. In terms of treatment we need to do both more and less. We need to treat more patients who could benefit from medication but are not receiving adequate treatment. We need to develop new preventives to treat the sufferer of frequent headache whose disability load is truly dreadful, while at the same time guarding against using medications designed for intermittent acute use (triptans, ergotamine and analgesics) as pseudo-preventives -- primum non nocere! Lastly, we must spread the message that migraine is a genetically determined problem which is reasonably well characterised neurobiologically. Migraine involves dysfunction of brainstem and diencephalic areas normally involved in controlling pain and other sensory information and results in activation of very specific trigeminovascular pain pathways which are well defined and understood. The future is bright -- a good history, meticulous physical examination, clear diagnosis and explanation, and management directed at restoring ability to function is exactly what we can offer and, I think, exactly what patients want. Peter J Goadsby Professor of Clinical Neurology, Institute of Neurology University Department of Clinical Neurology National Hospital for Neurology and Neurosurgery Queen Square, London, UK Disclosure statement: In recent times the author has advised, collaborated with, and spoken at meetings organised by various companies, including Allergan, Almiral-Prodesfarma, AstraZeneca, BristolMyersSquibb, GlaxoWellcome, MSD, Pfizer, Pharmacia-Upjohn, Sandoz, and SmithKlineBeecham, which manufacture compounds referred to in this article or have an interest in developing compounds for the treatment of various primary headache syndromes. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNLA4. Cell 1996; 87: 543-552. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nat Med 1995; 1: 658-660. May A, Bahra A, Buchel C, et al. Hypothalamic activation in cluster headache attacks. Lancet 1998; 351: 275-278. Anthony M, Hinterberger H, Lance JW. Plasma serotonin in migraine and stress. Arch Neurol 1967; 16: 544-552. Doenicke A, Brand J, Perrin VL. Possible benefit of GR43175, a novel 5-HT1-like receptor agonist, for the acute treatment of severe migraine. Lancet 1988; 1: 1309-1311. Ferrari MD. The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med 1991; 325: 316-321. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8(Suppl 7): 1-96. Goadsby PJ. A triptan too far. J Neurol Neurosurg Psychiatry 1998; 64: 143-147. Goadsby PJ. 5-HT1B/1D agonists in migraine: comparative pharmacology and its therapeutic implications. CNS Drugs 1998; 10: 271-286. Kaube H, May A, Diener HC, Pfaffenrath V. Sumatriptan misuse in daily chronic headache. BMJ 1994; 308: 1573-1574. Limmroth V, Kazarawa S, Fritsche G, Diener HC. Headache after frequent use of new serotonin agonists zolmitriptan and naratriptan. Lancet 1999; 353: 378. Friedman AP, Brazil P. Ergotamine tolerance in patients with migraine. J Am Med Assoc 1955; 157: 881-884. Diener HC. A personal view of the classification and definition of drug dependence headache. Cephalalgia 1993; 13: 68-71. Tfelt-Hansen P, Saxena PR, Dahlof C, et al. Ergotamine in the acute treatment of migraine - a review and European consensus. Brain 2000; 123: 9-18. Make a comment

Peter J Goadsby

Editorial Preventing stroke: what is the real progress? At last, stroke prevention is high on the political and public health agenda MJA 1999; 171: 285-286 National Stroke Awareness Week (27 September - 3 October) is a pertinent time to review recent progress in stroke prevention and awareness in the past few years. In Australia, stroke continues to be a major public health issue.1 More than 40 000 Australians each year experience a stroke, nearly a third of which are fatal.1,2 Another third of stroke sufferers become disabled, and stroke victims make up nearly one in four of Australia's chronic disabled population.1 The annual total cost of caring for stroke victims is at least $1.67 billion,2 a figure which will continue to rise with ageing of Australia's population. It is estimated that there will be at least 70 000 new stroke patients each year by 2016.2Nevertheless, real progress has been made in the past few years in several areas: The emergence, and application in clinical practice, of sound evidence for the effectiveness of several stroke-prevention strategies in people at high risk; A decline in stroke incidence due to effective prevention measures; and A willingness of Federal, State and Territory governments to take a more active role in stroke prevention. Strategies for reducing the social and economic burden of stroke are summarised in the Box. The effectiveness of primary stroke prevention in the entire population is difficult to ascertain. Mortality statistics are the only routinely collected data for measuring and monitoring the burden of stroke nationally, and between 1986 and 1997 the stroke mortality rate for Australian men and women fell by 3.2% and 3.5% per year, respectively. Since 1970 there has been a 68% overall reduction in stroke mortality.1,3 The recent Perth Community Stroke Study (PCSS)4 found that the decline in stroke mortality was due to a reduced incidence of stroke rather than an improvement in survival or a change in casemix (eg, a reduced proportion of lethal intracerebral haemorrhages). This fall in stroke incidence is likely to be due to a decline in the prevalence of important causal and modifiable risk factors. The PCSS identified several of these risk factors, many of which are well established, and some of which require confirmation in future studies.5 These include previous stroke or transient ischaemic attack, cigarette smoking, excess alcohol intake (> 60 g daily), a history of hypertension, diabetes mellitus, meat consumption (more than four times weekly), and adding salt to food. Over the past one to two decades, the Australian Institute of Health and Welfare (AIHW) has documented a significant decline in the population prevalence of many of these risk factors (ie, hypertension, smoking, total dietary fat intake, and saturated fat as a proportion of total energy intake).1 Although it is not possible to prove that health promotion programs, government legislation and the decline in prevalence and mean level of risk factors have been directly responsible for the reduction in stroke incidence in Australia, I believe the above data endorse the concept and power of the population approach to stroke prevention. It might be argued that the population approach impinges on all for the benefit of relatively few.3 However, most of us are prepared to adopt lifestyle behaviours (eg, wearing of seatbelts, application of sunscreen lotion) which reduce harm to the population as a whole, and stroke prevention measures would be similar in principle. Moreover, given that the risk of stroke in the next 40 years for a 45-year-old is one in four for men and one in five for women,1 there is also a reasonable chance of individual benefit in adopting lifestyle changes aimed at reducing the risk of stroke. The push for greater stroke awareness in our society has received a considerable boost in recent years from a greater involvement of governments in promoting awareness of stroke and facilitating educational programs aimed at reducing the risk of stroke. The involvement is exemplified by: Establishment of the National Stroke Foundation, which published a National Stroke Strategy and Victorian Stroke Strategy in 1997;9 Establishment by the New South Wales Health Department of the NSW Stroke Project;10 Endorsement by Australian health ministers of heart, stroke and vascular disease as one of the five National Health Priority Areas (NHPAs). The recent NHPA report, Cardiovascular Health 1998,11 highlights the strategies that are in place (and to be developed) to prevent stroke by improving awareness, lifestyle behaviours, and risk factor profiles of Australians, and improving outcomes for those with symptomatic disease through optimal diagnosis, management, rehabilitation, and community care.11 It also emphasises the ongoing role of the AIHW in operating a national system to monitor stroke incidence, pathology, risk factors, treatments, care, outcome (for patients and carers) and costs. At last, stroke is high on the political and public health agenda, but it is crucial that the commitment be maintained to measuring, monitoring and reducing the burden of stroke by widespread adoption of evidence-based practices and other strategies outlined in the NHPA report.11 Otherwise, we will soon experience a needless epidemic of stroke, with its legacy of death, disability and mounting cost. Graeme J Hankey Consultant Neurologist, and Head of Stroke Unit, Royal Perth Hospital Clinical Associate Professor, Department of Medicine, University of Western Australia, Perth, WA Email: gjhankeyATcyllene.uwa.edu.au Australian Institute of Health and Welfare (AIHW). Heart, stroke and vascular diseases, Australian facts. Canberra: AIHW/Heart Foundation of Australia, 1999. (AIHW Catalogue No. CVD 7; Cardiovascular Disease Series No. 10.) National Health and Medical Reseach Council (NHMRC). Clinical Practice Guidelines. Prevention of stroke: the role of anticoagulants, antiplatelet agents and carotid endarterectomy. Canberra: NHMRC/Australian Government Publishing Service, 1997: 3-4. Rose G. The strategy of preventive medicine. Oxford: Oxford University Press, 1992: 29-52, 64-106. Jamrozik K, Broadhurst R, Lai N, et al. Trends in the incidence, severity and short-term outcome of stroke in Perth, Western Australia. Stroke 1999. In press. Jamrozik K, Broadhurst RJ, Anderson CS, Stewart-Wynne EG. The role of lifestyle factors in the etiology of stroke. A population-based case-control study in Perth, Western Australia. Stroke 1994; 25: 51-59. Hankey GJ. Stroke: how large a public health problem, and how can the neurologist help? Arch Neurol 1999; 56: 748-754. Hankey GJ, Warlow CP. Treatment and secondary prevention of stroke: evidence, cost, and effects on individuals and populations. Lancet 1999. In press. Gorelick PB, Sacco RL, Smith DB, et al. Prevention of a first stroke. A review of guidelines and a multidisciplinary consensus statement from the National Stroke Association. JAMA 1999; 281: 1112-1120. National Stroke Strategy. Melbourne: National Stroke Foundation, 1997. Stroke in NSW. Priorities and strategies for better care. Sydney: NSW Health Department, 1997. Commonwealth Department of Health and Aged Care and Australian Institute of Health and Welfare. National Health Priority Area Report: Cardiovascular Health 1998. Canberra: Australian Institute of Health and Welfare, 1999. (Catalogue No. PHE9.) Strategies for reducing the burden of stroke and stroke recurrence (in increasing order of potential impact)6,7 Effective treatment of acute stroke6,7 Organised care in a stroke unit by a multidisciplinary team Aspirin 300 mg for acute ischaemic stroke tPA (may be effective, but possibly hazardous, and therefore is not currently registered in Australia or Europe for stroke treatment6) Secondary prevention of recurrent stroke in patients with transient ischaemic attacks (TIAs) and stroke (in decreasing order of cost-effectiveness)7* Treatment of high blood pressure with a diuretic or β-blocker Aspirin, aspirin + dipyridamole, or clopidogrel for patients in sinus rhythm Anticoagulation with warfarin for patients with atrial fibrillation Carotid endarterectomy for patients with severe stenosis of the internal carotid artery on the symptomatic side Primary prevention of stroke among people at high risk of stroke (eg, those with severe hypertension or atrial fibrillation)3,8 Treatment of high blood pressure with a diuretic or β-blocker "Statins" to lower serum cholesterol levels in patients with symptomatic coronary artery disease or hypercholesterolaemia Anticoagulation with warfarin for patients with atrial fibrillation and specific risk factors (age > 65 years, diabetes, hypertension, TIA or stroke), or patients with recent myocardial infarction who have atrial fibrillation, decreased left ventricular ejection fraction, or left ventricular thrombus Primary prevention of stroke in the general population by reducing risk factors3,6Reducing consumption of meat, salt, saturated fat and alcohol Reducing prevalence of smoking Reducing prevalence of obesity Increasing physical activity Controlling hypertension and hypercholesterolaemia Controlling diabetes mellitus *Randomised trials of the effect of smoking cessation, other antihypertensive agents, and 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors ("statins") in secondary stroke prevention are either still in progress or yet to be undertaken. Back to text

Graeme J Hankey

Editorial Migraine: then and now Better understanding of the neurobiology of migraine is leading to better treatment MJA 1996; 164: 519-520 Migraine is debilitating for its victims and frustrating for their friends and relatives. The Australian National Health Survey of 57 000 people in 1989-1990 found that 12.2% had experienced a headache in the preceding two weeks.1 Extrapolation to the entire Australian population implies that 280 000 people suffered a migraine attack and two million some lesser form of headache in that two-week period. The annual cost of migraine to the community, considering loss of productivity and cost of medical services, has been estimated at $302-$721 million by the Centre for Applied Economic Research, University of New South Wales.2National Migraine Week (12-18 May) may help to increase public awareness of this problem. In addition, the Migraine Foundation, a subsidiary of the Australian Brain Foundation, has recently been established to promote education and to encourage research and the formation of self-help groups in the community. When is a headache a migraine? Whether migraine has a place at one end of a headache spectrum or is a separate entity remains controversial. The International Headache Society has established criteria for the diagnosis of migraine, to standardise headache classification for surveys and clinical trials.3The Classification Committee's general description of migraine is "an idiopathic headache disorder manifesting in attacks lasting 4-72 hours", with the characteristics of common unilateral location, pulsating quality, moderate or severe intensity, aggravation by physical activity and association with nausea and photophobia. Nevertheless, a third of migraine headaches are bilateral, and not all throb or are accompanied by nausea and photophobia. About 25% of those affected describe premonitory symptoms the night before -- a feeling of elation, craving for sweet foods or excessive yawning. Between 25% and 40% experience a visual aura at some time, but only 10% describe typical fortification spectra (zigzag visual hallucinations) or spreading scintillating scotomas. Such neurological symptoms usually precede the headache, but may occur without an ensuing headache or may appear while a headache is in progress. However, most migraine headaches occur without such symptoms. Varieties of migraine are designated hemiplegic, basilar, ophthalmoplegic or retinal, depending on the area of the brain rendered ischaemic. A migraine headache lasting longer than 72 hours is termed "status migrainosus". Neurological symptoms persisting for more than seven days indicate a migrainous infarction. Genetic factors contribute about half of the susceptibility to migraine, and the gene for some kinships with familial hemiplegic migraine has been localised to chromosome 19.4 Neurobiology of migraine Modern techniques have improved our knowledge of both aura and headache mechanisms. Aura: Regional cerebral blood flow studies show a reduction in cortical perfusion, starting in the parieto-occipital region during a visual aura and spreading forward at 2-3 mm/min. This corresponds to the speed at which fortification spectra appear to move over the field of vision and that of "spreading cortical depression" observed by Leâo as an artefact in experimental animals in the 1940s.5 Recently, magnetic resonance imaging and positron emission tomography (PET) showed a similar spreading pattern of diminished metabolism in a patient with migraine with blurred vision but no classical aura.6 Although needing confirmation, this raises the possibility of cortical oligaemia in migraine attacks that lack an aura; this would account for the impaired vision, loss of concentration and poor memory that often accompany migraine headache. Headache pain: Since the work of Wolff and his colleagues in the 1940s and 1950s, dilatation of the superficial temporal artery and its branches has been regarded as the main cause of headache pain. However, recent studies have shown that this applies to only about a third of migraine patients. Measurements of velocity of blood flow with transcranial Doppler ultrasound have shown that the middle cerebral artery dilates during migraine headache and returns to normal when the headache resolves after the injection of sumatriptan.7 Cerebral oedema may also be a feature of some migraine attacks, as there have been two reports of skull defects bulging during the headache phase.8 "Neurogenic inflammation" (with extravasation of protein from dural vessels) has been implicated, brought about by release of vasodilator peptides, such as calcitonin gene-related peptide (CGRP) and substance P.9,10 This effect can be blocked by sumatriptan and dihydroergotamine. It is also possible that the blood-brain barrier breaks down during migraine headache, allowing access of drugs that are normally excluded. When sumatriptan is administered during the aura phase it does not prevent the ensuing migraine headache, despite its prompt action once headache is established, suggesting that it can enter the brain only after the headache starts. How can we link the initiating cerebral events and the vascular changes? Stimulation of the brainstem nuclei, locus coeruleus and raphe dorsalis has been shown in animals to alter both intracranial and extracranial blood flow.11 In humans, some patients with implanted electrodes which stimulate the periaqueductal grey matter or thalamus for relief of bodily pain have developed migraine-like headaches, some associated with visual symptoms.12 PET scans during and after migraine headache have shown increased metabolic activity in the region of the periaqueductal grey matter and locus coeruleus on the side of the migraine headache, which persisted after the headache.13 What has happened to the "serotonin story"? It is now thought that the discharge of serotonin (5-hydroxytryptamine, 5-HT) by platelets at the onset of migraine headache14 may reflect similar changes in the central nervous system, as serotonin plays a key role in pain control. Serotonin is also a potent vasoconstrictor in the cranial circulation. Increase in knowledge of the many 5-HT receptors has led to the synthesis of agents which act as agonists of these receptors. Prophylactic medications, such as pizotifen and methysergide, act predominantly on 5-HT2 receptors in the central nervous system. The newest antimigraine drug, sumatriptan, is a highly selective agonist of the D-subtype of 5-HT1 receptors. It constricts cranial arteries, interferes with the release of vasodilator peptides and may also have central actions (as yet unknown), if, as has been proposed, the blood-brain barrier breaks down during migraine headache. Already other 5-HT1D agonists, such as 311C90 (zolmitriptan) and MK462, are undergoing clinical trials for the management of migraine headache. Continued research on these drugs and on the receptor sites for serotonin and other neurotransmitters involved in the migraine syndrome promises new therapeutic avenues in the treatment of migraine. James W Lance Consultant Neurologist, Institute of Neurological Sciences Prince Henry and Prince of Wales Hospitals, Sydney, NSW Australian Bureau of Statistics. National Health Survey: summary of results. 1989-1990. Canberra: ABS, 1991. (Catalogue No. 4364.0.) Parry TG. The prevalence and costs of migraine in Australia. Centre for Applied and Economic Research working paper. Sydney: CAER, University of New South Wales, 1992. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988; 8 Suppl 7: 13-96. Merikangas KR. Sources of genetic complexity of migraine. In: Sandler M, Ferrari M, Harnett S, editors. Migraine: pharmacology and genetics. London: Chapman and Hall, 1996: 254-274. Leâo AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol 1944; 7: 359-390. Woods RP, Iacoboni M, Mazziotta JC. Bilateral spreading cerebral hypoperfusion during spontaneous migraine headache. N Engl J Med 1994; 331: 1689-1692. Friberg L, Olesen J, Iversen HK, Sperling B. Migraine pain associated with middle cerebral artery dilatation: reversal by sumatriptan. Lancet 1991; 338: 13-17. Lance JW. Swelling at the site of a skull defect during migraine headache. J Neurol Neurosurg Psychiatry 1995; 59: 641. Moskowitz MA, Cutrer EM. Trigeminovascular system and migraine. Semin Headache Manage 1996; 1: 7-9. Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 1993; 33: 48-56. Lance JW, Lambert GA, Goadsby PJ, Zagami AS. Contribution of experimental studies to understanding the pathophysiology of migraine. In: Sandler M, Collins GM, editors. Migraine: a spectrum of ideas. Oxford: Oxford University Press, 1990: 21-39. Raskin NH, Hosobuchi Y, Lamb S. Headache may arise from perturbation of brain. Headache 1987; 27: 416-420. Weiller C, May A, Limmroth V, et al. Brain stem activation in spontaneous human migraine attacks. Nature Med 1995; 1: 658-660. Anthony M, Hinterberger H, Lance JW. Serotonin in migraine and stress. Arch Neurol 1967; 16: 544-552. ©MJA 1999 © 1999 Medical Journal of Australia.

James W Lance